Description
Prulifloxacin was launched as the third fluoroquinone. It was introduced in
Japan as an oral treatment for urinary tract infections (UTls), respiratory tract infections
(RTls) and bacterial pneumoniae. It can be synthesized in 10 steps from commercially
available 3,4-difluoroaniline. Key steps involve the cyclization of 6,7-difluoro-rl-hydroxy-2-
thioquinoline-3carboxylic acid ethyl ester with 1 ,I-dibromomethane to give the
corresponding thiazeto-[3,2a]quinoline. Aromatic nucleophilic substitution of the 7-fluoro
atom with piperazine followed by hydrolysis of the ethyl ester and finally alkylation of the
piperazinyl moiety with 4-(bromomethyl)-5-methyl-l ,bdioxol-Bone complete the synthesis.
Prulifloxacin is a lipophilic prodrug, which is rapidly hydrolyzed to the corresponding Ndealkylated
piperazine, NM 394, by paraoxonase type enzymes in blood and liver following
intestinal absorption. The DNA gyrase inhibitor NM 394 accounts for all antimicrobial
activity: it shows a similar or greater activity against gram-positive bacteria compared to
ciprofloxacin, and a greater activity in the case of gram-negative bacteria. In clinical
studies, prulifloxacin has shown good efficacy against UTls and RTls. The drug is mainly
excreted in the urine and in the feces as unchanged NM 394, which has a plasma half-life
of approximately 8 h. Phototoxicity in animal models is less severe than with other
quinolones. Prulifloxacin is well tolerated with an adverse effect profile similar to that of
other fluoroquinolones.
Chemical Properties
Off-White Solid
Originator
Nippon Shinyaku (Japan)
Uses
Fluoroquinoline antibacterial; prodrug for active metabolite, Ulifloxacin. Antibacterial.
Uses
Prulifloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class. Prulifloxacin is a prodrug for active metabolite, Ulifloxacin. Antibacterial.
Definition
ChEBI: Prulifloxacin is a quinolone antibiotic and a fluoroquinolone antibiotic.
Pharmaceutical Applications
A lipophilic prodrug which is very rapidly metabolized by esterase into ulifloxacin, a 6-fluoro, 7-piperazinyl thiazetoquinoline.
Ulifloxacin is moderately active against Staph. aureus (MIC 0.4–0.8 mg/L) and inactive against Str. pneumoniae (MIC 2–8 mg/L) as well as against Enterococcus spp. Against Enterobacteriaceae (MIC 0.05–0.8 mg/L) and Ps. aeruginosa (MIC 0.2–0.8 mg/L) activity is similar to that of ciprofloxacin. It is active against fastidious Gram-negative bacilli, but not against anaerobes and non-fermentative Gram-negative bacilli. Activity against Acinetobacter spp. is modest.
Prulifloxacin is rapidly converted into ulifloxacin and after 3 h is no longer detected in blood. In volunteers receiving a single oral dose, peak plasma concentrations of 0.68 mg/L (300 mg dose) to 1.88 mg/L (for 400 mg dose) were attained between 0.67 and 1.25 h. The mean apparent elimination half-life was 8 h and the mean cumulative elimination rate in urine within 48 h was 31–46%. Other inactive metabolites account for 7% of the dose. Half the administered dose is eliminated in feces within 72 h as ulifloxacin and 4% as prulifloxacin. Protein binding is 45%.
Synthesis
The synthesis of
prulifloxacin (22)started with the treatment of 3,4-
difluoroaniline (183) with carbon disulfide in the presence of
TEA to give the triethylammonium dithiocarbamate, which
by reaction with ethyl chloroformate and TEA in
chloroform, was converted into isothiocyanate 184 in 74%
yield. Reaction of 184 with diethyl malonate in the presence
of KOH in dioxane yielded methylenemalonate 185
potassium salt, which was ethylated with ethyl sulfate in
ethanol to give compound 186 in excellent yield. 6,7-
Difluoroquinoline 187 was obtained with the highest yield
and regioselectivity when precursor 186 was heated in
refluxing xylene. To suppress the side reaction in the
subsequent chlorination, quinoline 187 was acylated to give
188 with acetyl chloride in chloroform. Chlorination of 188
with sulfuryl chloride gave compound 189 in 79% yield.
Compound 189 was treated with sodium acetate in THF to
afford cyclized compound 190, which was condensed with
piperazine in DMF to give compound 191. The hydrolysis
of ester 191 with KOH in hot t-butanol gave free acid 192,
which was finally condensed with 4-(bromomethyl)-5-
methyl-1, 3-dioxol-2-one (163) by treatment of potassium
bicarbonate in DMF to give prulifloxacin (22).
